A selective lesion of the 5-HT axon terminals significantly decreases the number of specific high affinity recognition sites labelled by 3H-imipramine and prevents the down regulation of Alpha-adrenergic and of 5-HT2 recognition sites elicited by repeated daily injections of imipramine (IMI) and desmethylimipramine (DMI). Moreover after daily injections of IMI and DMI for 2-3 weeks the max of 3H-IMI binding is decreased while the Vmax of 3H-5-HT uptake in hippocampus slices is increased. These findings suggest: 1) a relevant pharmacological role of the 3H-IMI recognition site in mediating some of the neurochemical effects elicited by chronic IMI treatment 2) a possible physiological role of the 3H-IMI recognition on sites in modulating the gain of the 5HT reuptake and thereby the 5HT synaptic transmission; 3) the existence of a putative endogenous ligand (endacoid) for the 3H-IMI binding site which physiological modulates the 3H-5HT reuptake. A nonpeptide thermostable putative endacoid which inhibits in a dose-dependent manner. 3H-IMI binding and 5HT uptake very partially purified from rat brain. HPLC retention time and other chemical physical properties differentiate it from 5HT and a series of indole-alkyl devivatives including tryptoline, 5-hydroxy and 5-methoxy-tryptoline. Crude synaptic membrane from rat brain contain also specific and high affinity reception sites for 3H-Mianserin an atypical antidepressant. The 3H-Mianserin reception sites appear to be different from the 5HT2 recognition sites labelled by 3H-Ketausei: 5HT axon terminals lesion and pharmacological treatments elicita different modifications upon the two binding sites. The 3H-Mianserin recognition site is proposed to be part of the supramolecular organization of the 5HT2 receptor complex are involved in the modulation of the seronergic synaptic transmission.